The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice
Zhang, Donna D.
AffiliationUniv Arizona, Dept Pharmacol & Toxicol
MetadataShow full item record
CitationYang, Yi & Kong, Sinyi & Zhang, Yana & Melo-Cardenas, Johanna & Gao, Beixue & Zhang, Yusi & D. Zhang, Donna & Zhang, Bin & Song, Jianxun & Thorp, Edward & Zhang, Kezhong & Zhang, Jinping & Fang, Deyu. (2018). The endoplasmic reticulum-–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B- cell development in mice. Journal of Biological Chemistry. 293. jbc.RA117.001267. 10.1074/jbc.RA117.001267.
JournalJOURNAL OF BIOLOGICAL CHEMISTRY
Rights© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractHumoral immunity involves multiple checkpoints that occur in B cell development, maturation, and activation. The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy-chain gene, and sSignalsing through the pre-BCR are required for the differentiation of pre-B cells into immature B cells. However, the molecular mechanisms controlling the pre-BCR expression and signaling strength remain undefined. Herein, we probed the role of the endoplasmic reticulum-associated, stress-activated E3 ubiquitin ligase HMG-CoA reductase degradation 1 (Hrd1) in B cell differentiation. Using mice with a specific Hrd1 deletion in pro-B cells and subsequent B cell developmental stages, we showed that the E3 ubiquitin ligase Hrd1 governs a critical checkpoint during B cell development. We observed that Hrd1 is required for degradation of the pre-BCR complex during the early stage of B cell development. As a consequence, loss of Hrd1 in the B cell lineage resulted in increased pre-BCR expression levels and a developmental defect in the transition from large to small pre-B cells. This defect, in turn, resulted in reduced fewer mature B cells in bone marrow and peripheral lymphoid organs. Our results revealed a novel critical role of Hrd1 in controlling a critical checkpoint in B cell-mediated immunity and suggest that Hrd1 may functioning as an E3 ubiquitin ligase of the pre-BCR complex.
Note12 month embargo; published online: 15 June 2018
VersionFinal published version
SponsorsNational Institutes of Health [AI079056, AI108634, AR006634]; National Natural Science Foundation of China (NSFC) [81600784, 31270939, 81471526, 81771667]; Training Program of the Major Research Plan in regional immunology of the National Natural Science Foundation of China ; Natural Science Foundation of Jiangsu Province [BK20170349]; postdoctoral foundation of China; Social development project of Jiangsu Province Grant [BE2016676]; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences of Soochow University
- Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas.
- Authors: Kong S, Yang Y, Xu Y, Wang Y, Zhang Y, Melo-Cardenas J, Xu X, Gao B, Thorp EB, Zhang DD, Zhang B, Song J, Zhang K, Zhang J, Zhang J, Li H, Fang D
- Issue date: 2016 Sep 13
- The Sel1L-Hrd1 Endoplasmic Reticulum-Associated Degradation Complex Manages a Key Checkpoint in B Cell Development.
- Authors: Ji Y, Kim H, Yang L, Sha H, Roman CA, Long Q, Qi L
- Issue date: 2016 Sep 6
- A hypomorphic IgH-chain allele affects development of B-cell subsets and favours receptor editing.
- Authors: Brenner S, Drewel D, Steinbart T, Weisel F, Härtel E, Pötzsch S, Welzel H, Brandl A, Yu P, Mudde GC, Schweizer A, Nitschke L, Winkler TH
- Issue date: 2011 May 27
- Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum.
- Authors: Kikkert M, Doolman R, Dai M, Avner R, Hassink G, van Voorden S, Thanedar S, Roitelman J, Chau V, Wiertz E
- Issue date: 2004 Jan 30
- Characterization of protein complexes of the endoplasmic reticulum-associated degradation E3 ubiquitin ligase Hrd1.
- Authors: Hwang J, Walczak CP, Shaler TA, Olzmann JA, Zhang L, Elias JE, Kopito RR
- Issue date: 2017 Jun 2
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